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Description of key information

A study in mice indicated that methyl isobutyl ketone (MIBK) may be an agonist for the constitutive androstane receptor (CAR) in liver mice.  This was evaluated following inhalation exposure to 1800 ppm MIBK for 7 days.  The study authors noted that this mechanism of action for liver carcinogenicity is not relevant to humans.
A study in rats, demonstrated that MIBK may exert effects on the male rat kidney via an alpha-2u-globulin mechanism. As well, this mecanism of action for kidney carcinogenicity, which is species and male specific, is not relevant to humans.

Additional information

The key studies for this group of substances (DIBC, DIBK, MIBK and MIBC) are two 2 -year carcinogenicity studies in mice and rats using MIBK. These studies showed the potential for MIBK to produce kidney tumours in rats and liver tumours in mice. Given the absence of any genotoxicity for this group of substances it was considered that the mode of action involved a non-genotoxic, threshold mechanism. In addition, the relevance of these tumour types to humans has been questioned due to the data available on the potential mode of action. The below studies were conducted to understand whether the mode of action for MIBK carcinogenicity in liver and kidney was in fact relevant for humans. In addition to these studies, additional data are also being generated to provide further support for the mechanism of tumour formation and its lack of relevance to humans.

Given the structural similarities and consistent toxicological profiles within this group of substances it is considered plausible that all members could produce toxicity in the livers and kidneys that may ultimately result in tumor formation in chronic studies. However, it therefore follows that their structural similarities and common metabolic pathways would also support a common mode of action, and thus the data that support a lack of human relevance for MIBK carcinogenicity also support the lack of relevance for the other members of the group.

Studies on the mode of action for carcinogenicity

In a non-guideline and non-GLP study, the effects of methyl isobutyl ketone (MIBK) on the mouse liver were evaluated (The Dow Chemical Company, 2009). Male B6C3F1 mice were implanted with 5-bromo-2’deoxyuridine (BrdU) pumps and then exposed to 0 or 1800 ppm (n=6/group) of MIBK via whole-body inhalation for 6 hours/day for 7 days. In-life assessments included clinical signs and body weights. Mice were euthanized and assessed for clinical chemistry, gene expression analysis of the upper third of the left liver lobe, liver histopathological examination and BrdU proliferation analysis, and liver enzyme activity. There were no treatment-related effects noted for clinical signs, body weights, liver weights, or clinical chemistry assessments. Treatment-related findings included very slight hepatocytes hypertrophy with increased cytoplasic eosinophilia in the centrilobular/midzonal regions of the hepatic lobule which were consistent with increased smooth endoplasmic reticulum and induction of cytochrome P450 enzymes. CYP2B10 transcript levels increased 4-fold and CYP4A10 decreased 5.56-fold. This was verified by increased CYP2B10 enzyme activity (PROD) and hepatocyte proliferation. These responses are commonly observed following activation of constitutive androstane receptor (CAR) and indicate that MIBK may be an agonist ligand for CAR in mice and share a similar mode of action to that of Phenobarbital in mice. The study authors noted that this mechanism of action is not relevant to humans.

 

In another non-guideline and non-GLP study, the effects of MIBK exposure on Fischer 344 rat kidneys were assessed (Borhoff et al., 2009). Male and female rats were administered corn oil, 1000 mg/kg bw/day MIBK, or d-limonene (positive control) for 10 consecutive days by oral gavage (4/sex/group). Rats were euthanized 24 hours after the last dose, and the left kidney evaluated for histological changes in hyaline droplet accumulation, alpha-2u- nephropathy, and proliferating cell nuclear antigen. The right kidney was assessed for total protein and alpha-2u-globulin using an enzyme-linked immunosorbent assay (ELISA). There were no changes in body weight gain, terminal body weights, or total kidney weight. The kidney:body weight ratio was increased slightly in male and female rats compared to controls. Changes observed in MIBK-treated male rats were similar or slightly milder than those observed in d-limonene-treated rats. Findings included mild to moderate hyaline droplet accumulation, positive Mallory’s Heidenhain staining, more intense alpha-2u-globulin staining compared to untreated controls, and a statistically significant increase in renal cell proliferation. There were no changes noted in any of the females administered MIBK. These results provide support that MIBK exerts renal effects in male rats through an alpha-2u-mediated mechanism. This mechanism of action is not considered relevant to human risk assessment.